Background and Objective: Limbal stem cell deficiency (LSCD) is characterized by the insufficiency of limbal stem cells to maintain the corneal epithelium. Severe cases of LSCD may be treated with limbal transplantation from healthy autologous or allogeneic limbal tissue. Multiple cell-based therapies have been studied as alternative treatments to improve success rates and minimize immunosuppressive regimens after allogeneic transplants. In this review, we describe the success rates, and complications of different cell-based therapies for LSCD. We also discuss each therapy’s relative strengths and weaknesses, their history in animal and human studies, and their effectiveness compared to traditional transplants.

Methods: PubMed was searched for publications using the terms LSCD, cell-based therapy, cultivated limbal epithelial transplantation (CLET), cultivated oral mucosal epithelial transplantation (COMET),and mesenchymal stem cells from 1989 to August 2022. Inclusion criteria were English language articles.Exclusion criteria were non-English language articles.

Key Content and Findings: current cell-based therapies for LSCD are CLET and non-limbal epithelial cells. Non-limbal epithelial cell methods include COMET, conjunctival epithelial autografts, and mesenchymal stem/stromal cells (MSCs). Moreover, several alternative potential sources of non-limbal cells have described, including induced pluripotent stem cells (iPSCs), human embryonic stem cells (hESCs),human dental pulp stem cells, hair follicle bulge-derived epithelial stem cells, amniotic membrane epithelial cells, and human umbilical cord lining epithelial cells.

Conclusions: Cell-based therapies are a promising treatment modality for LSCD. While CLET is currently the only approved cell-based therapy and is only approved in the European Union, more novel methods have also been shown to be effective in human or animal studies thus far. Non-limbal epithelial cells such as COMET are also an alternative treatment to allogeneic transplants especially as a surface stabilizing procedure. iPSCs are currently being studied in early phase trials and have the potential to revolutionize the way LSCD is treated. Lastly, cell-based therapies for restoring the limbal niche such as mesenchymal stem cells have also shown promising results in the first human proof-of-concept study. Several potential sources of non-limbal cells are under investigation.

Background: A variety of experimental animal models are used in basic ophthalmological research to elucidate physiological mechanisms of vision and disease pathogenesis. The choice of animal model is based on the measurability of specific parameters or structures, the applicability of clinical measurement technologies, and the similarity to human eye function. Studies of eye pathology usually compare optical parameters between a healthy and altered state, so accurate baseline assessments are critical, but few reports have comprehensively examined the normal anatomical structures and physiological functions in these models.

Methods: Three cynomolgus monkeys, six New Zealand rabbits, ten Sprague Dawley (SD) rats, and BALB/c mice were examined by fundus photography (FP), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT).

Results: Most retinal structures of cynomolgus monkey were anatomically similar to the corresponding human structures as revealed by FP, FFA, and OCT. New Zealand rabbits have large eyeballs, but they have large optic disc and myelinated retinal nerve fibers in their retinas, and the growth pattern of retinal vessels were also different to the human retinas. Unlike monkeys and rabbits, the retinal vessels of SD rats and BALB/c mice were widely distributed and clear. The OCT performance of them were similar with human beings except the macular.

Conclusions: Monkey is a good model to study changes in retinal structure associated with fundus disease, rabbits are not suitable for studies on retinal vessel diseases and optic nerve diseases, and rats and mice are good models for retinal vascular diseases. These measures will help guide the choice of model and measurement technology and reduce the number of experimental animals required.

Abstract: The disease burden of diabetic retinopathy (DR) is tremendous around the world. While DR is correlated with hemoglobin A1c (HbA1c) and duration of diabetes, genetic differences likely account for variation in susceptibility to DR. DR is a polygenic disorder with demonstrated heritability. However, linkage and admixture analyses, candidate gene association studies, and genome-wide association studies (GWAS) have not identified many loci for DR that can be consistently replicated. Larger, collaborative, multi-ethnic GWAS are needed to identify common variants with small effects. Rigorous defining of controls groups as patients with a long duration of diabetes without DR, and case groups as patients with severe DR will also aid in finding genes associated with DR. Replication in independent cohorts will be key to establishing associated loci for DR. Investigations of mitochondrial DNA and epigenetics in DR are ongoing. Whole exome sequencing presents new opportunities to identify rare variants that might be implicated in DR development. Continued research in the genetic epidemiology of DR is needed, with the potential to elucidate pathogenesis and treatment of an important disease.

Abstract: Animals promote their survival by avoiding rapidly approaching objects that indicate threats. It is believed that looming cues are detected by retinal ganglion cells (RGCs) that project to the superior colliculus (SC). However, the exact type of RGC that transmits looming-related signals remains unclear. Here we identify a specific transient type of RGCs that controls mouse looming-evoked defensive response by sending axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABA neurons and in turn inhibit serotonin neurons. Moreover, optogenetically stimulating serotonin neurons reduces looming-evoked defensive behaviors. Thus, a dedicated population of RGCs detects rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how DRN and SC work in concert to extract and translate visual threats into defensive behavioral responses.

Abstract: Dopamine is known as a key molecule in retinal signaling pathways regulating visually guided eye growth, as evidenced by reduced retinal dopamine levels in various species when experimental myopia is generated. However, in C57BL/6 mice our recent work demonstrated that neither retinal dopamine levels, retinal tyrosine hydroxylase (rate-limiting enzyme in dopamine synthesis) levels, nor dopaminergic amacrine cell density/morphology, were altered during the development of form-deprivation myopia (FDM). These results suggest that retinal dopamine is unlikely associated with FDM development in this mouse strain. The role of dopamine in refractive development was further explored in this mouse strain when retinal dopamine levels were reduced by intravitreal injections of 6-OHDA, a neurotoxin that specifically destroys dopaminergic neurons. The dose was so chosen that retinal dopamine levels were reduced, but no significant changes in electroretinographic responses were detected. 6-OHDA induced significant myopic shifts in refraction in a dose-dependent manner, suggesting the involvement of dopamine in normal refractive development. Biometric measurements of ocular dimensions revealed that 6-OHDA resulted in a shorter axial length and a steeper cornea, while form-deprivation led to a longer axial length without changing the corneal radius of curvature. These results strongly suggest that in addition to the dopamine-independent mechanism, a dopamine-dependent mechanism works for refractive development. We have obtained evidence, suggesting that the dopamine-independent mechanism might be related to intrinsically photosensitive retinal ganglion cells (ipRGCs). Firstly, selective ablation of ipRGCs with an immunotoxin resulted in myopic shifts in refraction. Secondly, form-deprivation induced less myopic shifts in animals with ipRGC ablation.

Abstract: Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients. This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level, though the actual mechanism of repair still needs further investigations. The immune system responds in several ways upon photoreceptor engraftment, resulting in T-cell and macrophage infiltrations and, consequently, decrease in graft survival. Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting. Conversely, the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms. Here, Neves and colleagues explored the potential of cross-species studies and, to a certain extent, the concept of a protective immune system in retinal degeneration and therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF) was identified in this study as a novel factor that, by modulating the immune system, can slow down photoreceptor degeneration and improve transplantation outcome.